Treatment of pulmonary dysfunction with 15-ketoprostaglandin compounds

ABSTRACT

A method for treatment of a pulmonary dysfunction which comprises administering, to a subject in need of such treatment, a 15-ketoprostaglandin compound in an amount effective in treatment of the pulmonary dysfunction.

This is a continuation of application No. 07/616,955 filed Nov. 21, 1990now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for treatment of a pulmonarydysfunction which comprises administering a 15-ketoprostaglandincompound to a subject.

Prostaglandins (hereinafter, prostaglandins are referred to as PGs) aremembers of a class of organic carboxylic acid that are contained inhuman and most other mammalian tissues or organs and that exhibit a widerange of physiological activities. Naturally occurring PGs possess as acommon structural feature the prostanoic acid skeleton: ##STR1## Somesynthetic analogues have somewhat modified skeletons. The primary PGsare classified based on the structural feature of the five-memberedcycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIsand PGJs, and also on the presence or absence of unsaturation andoxidation in the chain moiety as:

Subscript 1 - - - 13,14-unsaturated-15--OH

Subscript 2 - - - 5,6- and 13,14-diunsaturated-15--Oh

Subscript 3 - - - 5,6- 13,14- and 17,18-triunsaturated-15--OH

Further, PGFs are sub-classified according to the configuration ofhydroxy group at position 9 into α(hydroxy group being in the alphaconfiguration) and β(hydroxy group being in the beta configuration).

2. Background Information

JP-A-164512/1983 discloses the protecting action of15-cycloalkyl-6-oxo-PGE₁, 15-cycloalkyl-PGI₁ and I₂, 15-cycloalkyl-6.9α-nitrilo-PGI₁ and 15-cycloalkyl-6.9α-thio-PGI₁ and I₂from disorder of cells. JP-A-203911/1983 discloses the cell-protectingaction of certain 6-oxo-PGE₁ and PGI₁ having methyl group(s) at one ortwo of positions 15, 16, 17 and 20 and specific 15-cyclopentyl-PGI₁.JP-A-73522/1984 discloses that certain PGD₂ and PGE₁ derivatives may beused as an agent for treating anoxic disease of cranial nerves. Allthese compounds, however, do not belong to 15-keto-PGs or theirderivatives.

European Patent Application No. 0,310,305 describes that 15-keto-PGs canbe used as catharitics.

As a result of extensive studies about the biological properties of15-ketoprostaglandin compounds, the present inventors have discoveredthat these compounds are useful as an agent for treating damagedpulmonary function.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method for treatmentof a pulmonary dysfunction which comprises administering, to a subjectin need of such treatment, a 15-ketoprostaglandin compound in an amounteffective in treatment of the pulmonary dysfunction.

In a second aspect, the present invention provides a use of a15-ketoprostaglandin compound for the manufacture of a medicament fortreatment of a pulmonary dysfunction.

In a third aspect, the present invention provides a pharmaceuticalcomposition for treatment of a pulmonary dysfunction comprising a15-ketoprostaglandin compound in association with a pharmaceuticallyacceptable carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "pulmonary dysfunction" means all conditionshaving etiology based on or accompanied by insufficiency of gas exchangefunction in lungs, which are symptoms or diseases having connection witheither disorder of permeation of oxygen contained in expired gas intoresorptive epithelium, disorder of permeation from resorptive epitheliuminto blood via pulmonary capillary cells or disorder of uptake of oxygeninto red cells (i.e. combination with hemoglobin). Examples of saidsymptoms or diseases include dyspnea or hypopnea resulted fromphysiologically active substance (such as narcotic, toxicant etc),foreign-body inhalation, anthracemia, bronchocontriction attack inhypoxic condition (caused by smoke, dust, chemical irritant etc.),broncho-pulmonary injury, pulmonary contusion or shock; pulmonary edema,atelectasis, pulmonary thrombosis, pulmonary infarction, plumonaryfibrosis, pulmonary emphysema, bronchitis, bronchial asthma, adultrespiratory distress syndrome (ADRS), infantile respiratory distresssyndrome (IRDS), pulmonary stenosis, pulmonary congestion, pulmonaryhypertension, chronic obstructive lung disease, congenital heartdisease, bilateral carotid body enucleation, sudden infant deathsyndrome, uremia and central inhibition caused by narcotic oranesthetic.

As used herein, the term "treatment" or "treating" refers to any meansof control of a disease in a mammal, including preventing the disease,curing the disease, relieving the disease and arresting or relieving thedevelopment of the disease.

The term "15-ketoprostaglandin compounds", referred to as 15-keto-PGcompounds, include any prostaglandin derivatives which have an oxo groupin place of the hydroxy group at position 15 of the prostanoic acidnucleus irrespective of the presence or absence of the double bondbetween positions 13 and 14.

Nomenclature

Nomenclature of 15-keto-PG compounds herein uses the numbering system ofprostanoic acid represented in formula (A) shown above.

While formula (A) shows a basic skeleton having twenty carbon atoms, the15-keto-PG compounds used in the present invention are not limited tothose having the same number of carbon atoms. The carbon atoms inFormula (A) are numbered 2 to 7 on the α-chain starting from theα-carbon atom adjacent to the carboxylic carbon atom which is numbered 1and towards the five-membered ring, 8 to 12 on the said ring startingfrom the carbon atom on which the α-chain is attached, and 13 to 20 onthe ω-chain starting from the carbon atom adjacent to the ring. When thenumber of carbon atoms is decreased in the α-chain, the number isdeleted in order starting from position 2 and when the number of carbonatoms is increased in the α-chain, compounds are named as substitutedderivatives having respective substituents at position 1 in place ofcarboxy group (C-1). Similarly, when the number of carbon atoms isdecreased in the ω-chain, the number is deleted in order starting fromposition 20 and when the number of carbon atoms is increased in theω-chain, compounds are named as substituted derivatives havingrespective substituents at position 20. Stereochemistry of the compoundsis the same as that of above formula (A) unless otherwise specified.Thus, 15-keto-PG compounds having 10 carbon atoms in the ω-chain isnominated as 15-keto-20-ethyl-PGs.

The above formula expresses a specific configuration which is the mosttypical one, and in this specification compounds having such aconfiguration are expressed without any specific reference to it.

In general, PGDs, PGEs and PGFs have a hydroxy group on the carbon atomat position 9 and/or 11 but in the present specification the term"15-keto-PG compounds" includes PGs having a group other than a hydroxylgroup at position 9 and/or 11. Such PGs are referred to as9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PGcompounds.

As stated above, nomenclature of 15-keto-PG compounds is based upon theprostanoic acid. These compounds, however, can also be named accordingto the IUPAC naming system. For example,13,14-dihydro-15-keto-16R,S-fluoro-PGE₂ is(Z)-7-{(1R,2R,3R)-3-hydroxy-2-[(4R,S)-fluoro-3-oxo-1-octyl]-5-oxocyclopentyl}-hept-5-enoicacid. 13,14-dihydro-15-keto-16,16-difluoro-PGE₂ is(Z)-7-[(1R,2R,3R)-2-(4,4-difluoro-3-oxo-1-octyl-3-hydroxy-5-oxocyclopentyl]-hept-5-enoicacid. 13,14-dihydro-15-keto-20-ethyl-11-dehydroxy-11R-methyl-PGE₂ methylester is methyl7-{(1R,2S,3S)-3-methyl-2-[3-oxo-1-decyl]-5-oxocyclopenty}-hept-5-enoate.13,14-dihydro-6,15-diketo-19-methyl-PGE₂ ethyl ester is ethyl7-{(1R,2S,3S)-3-hydroxy-2-(7-methyl-3-oxo-1-octyl)-5-oxocyclopentyl}-6-oxo-heptanoate.13,14-dihydro-15-keto-20-ethyl-PGF₂α isopropyl ester is isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-decyl}-cyclopentyl]-hept-5-enoate. 13,14-dihydro-15-keto-20-methyl-PGF₂α methyl ester ismethyl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-{3-oxo-1-nonyl}-cyclopentyl]-hept-5-enonate.

Preferred Compounds

The 15-keto-PG compounds used in the present invention may be anyderivatives of PG insofar as they have an oxo group at position 15 inplace of the hydroxy group, and may have a double bond between positions13 and 14 (15-keto-PG subscript 1 compounds), two double bonds betweenpositions 13 and 14 as well as positions 5 and 6 (15-keto-PG subscript 2compounds), or three double bonds between positions 13 and 14, positions5 and 6 as well as positions 17 and 18 (15-keto-PG subscript 3compounds), and may have a single bond between positions 13 and 14(13,14-dihydro-15-keto-PG compounds).

Typical examples of the compounds used in the present invention are15-keto-PGA, 15-keto-PGD, 15-keto-PGE, 15-keto-PGF,13,14-dihydro-15-keto-PGA, 13,14-dihydro-15-keto-PGD,13,14-dihydro-15-keto-PGE, and 13,14-dihydro-15-keto-PGF, wherein PG isas defined above as well as their substitution products or derivatives.

Examples of substitution products or derivatives include esters at thecarboxy group at the alpha chain, pharmaceutically or physiologicallyacceptable salts, unsaturated derivatives having a double bond or atriple bond between positions 2 and 3 or positions 5 and 6,respectively, substituted derivatives having substituent(s) on carbonatom(s) at position 3, 5, 6, 16, 17, 19 and/or 20 and compounds havinglower alkyl or a hydroxy (lower) alkyl group at position 9 and/or 11 inplace of the hydroxy group, of the above PGs.

Examples of substituents present in preferred compounds are as follows:Substituents on the carbon atom at position 3, 17 and/or 19 includelower alkyl, for example, C₁₋₄ alkyl, especially methyl and ethyl.Substituents on the carbon atom at position 16 include lower alkyl e.g.methyl, ethyl etc., hydroxy and halogen atom e.g. chlorine, fluorine,aryloxy e.g. trifluoromethylphenoxy, etc. Substituents on the carbonatom at position 17 include halogen atom e.g. chlorine, fluorine etc.Substituents on the carbon atom at position 20 include saturated andunsaturated lower alkyl e.g. C₁₋₄ alkyl, lower alkoxy e.g. C₁₋₄ alkoxyand lower alkoxy (lower) alkyl e.g. C₁₋₄ alkoxy-C₁₋₄ alkyl. Substituentson the carbon atom at position 5 include halogen atom e.g. chlorine,fluorine etc. Substituents on the carbon atom at position 6 include oxogroup forming carbonyl. Stereochemistry of PGs having hydroxy, loweralkyl or lower (hydroxy) alkyl substituent on the carbon atom atposition 9 and/or 11 may be alpha, beta or mixtures thereof.

Said derivatives may have an alkoxy, phenoxy or phenyl group at the endof the omega chain where the chain is shorter than the primary PGs.

Especially preferred compounds are those having a lower alkyl e.g.methyl, ethyl etc., a halogen atom e.g. chloro, fluoro etc. at position16, those having a halogen atom e.g. chloro, fluoro etc. at position 17,those having a lower alkyl e.g. methyl, ethyl etc. at position 19, thosehaving a halogen atom e.g. chlorine, fluorine etc. at position 5, thosehaving an oxo group at position 6, those having a lower alkyl, e.g.methyl, ethyl, etc. at position 20 and those having phenyl or phenoxywhich are optionally substituted with halogen or haloalkyl at position16 in place of the rest of the alkyl chain.

A group of preferred compounds used in the present invention has theformula ##STR2## wherein X and Y are hydrogen, hydroxy, halo, loweralkyl, hydroxy(lower)alkyl, or oxo, with the proviso that at least oneof X and Y is a group other than hydrogen, and 5-membered ring may haveat least one double bond, Z is hydrogen or halo, A is --CH₂ OH, --COCH₂OH, --COOH or its functional derivative, B is --CH₂ --CH₂, --CH═CH-- or--C.tbd.C--, R₁ is bivalent saturated or unsaturated, lower or mediumaliphatic hydrocarbon residue which is unsubstituted or substituted withhalo, oxo or aryl, R₂ is saturated or unsaturated, lower or mediumaliphatic hydrocarbon residue which is unsubstituted or substituted withhalo, hydroxy, oxo, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,aryl or aryloxy.

In the above formula, the term "unsaturated" in the definitions for R₁and R₂ is intended to include at least one and optionally more than onedouble bond and/or triple bond isolatedly, separately or seriallypresent between carbon atoms of the main and/or side chains. Accordingto usual nomenclature, an unsaturation between two serial positions isrepresented by denoting the lower number of said two positions, and anunsaturation between two distal positions is represented by denotingboth of the positions. Preferred unsaturation is a double bond atposition 2 and a double or triple bond at position 5.

The term "lower or medium aliphatic hydrocarbon residue" refers to astraight or branched chain hydrocarbyl group having 1 to 14 carbon atoms(for a side chain, 1 to 3 carbon atoms being preferred) and preferably 2to 8 carbon atoms for R₁ and 6 to 12 carbon atoms for R₂.

The term "halo" denotes fluoro, chloro, bromo and iodo.

The term "lower" throughout the specification is intended to include agroup having 1 to 6 carbon atoms unless otherwise specified.

The term "lower alkyl" as a group or a moiety in hydroxy(lower)alkylincludes saturated and straight or branched chain hydrocarbon radicalscontaining 1 to 6, carbon atoms, e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl and hexyl.

The term "lower alkoxy" refers to the group lower-alkyl-O- wherein loweralkyl is as defined above.

The term "hydroxy(lower)alkyl" refers to lower alkyl as defined abovewhich is substituted with at least one hydroxy group, e.g.hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and1-methyl-1-hydroxyethyl.

The term "lower alkanoyloxy" refers to a group of the formula: RCO--O--wherein RCO-- is an acyl group formed by oxidation of a lower alkylgroup as defined above, e.g. acetyl.

The term "cyclo(lower)alkyl" refers to a cyclic group formed bycyclization of a lower alkyl group as defined above.

The term "aryl" includes unsubstituted or substituted aromaticcarbocyclic or heterocyclic (preferably monocyclic) groups, e.g. phenyl,tolyl, xylyl and thienyl. Examples of substituents are halo andhalo(lower)alkyl wherein halo and lower alkyl being as defined above.

The term "aryloxy" refers to a group of the formula: ArO-- wherein Ar isaryl as defined above.

The term "functional derivative" of carboxy as A includes salts(preferably pharmaceutically acceptable salts), esters and amides.

Suitable "pharmaceutically acceptable salts" includes conventionalnon-toxic salts, and may be a salt with an inorganic base, for examplean alkali metal salt (e.g. sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.),ammonium salt, a salt with an organic base, for example, an amine salt(e.g. methylamine salt, dimethylamine salt, cyclohexylamine salt,benzylamine salt, piperidine salt, ethylenediamine salt, ethanolaminesalt, diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt,procaine salt, caffeine salt, etc.), a basic amino acid salt (e.g.arginine salt, lysine salt, etc.), tetraalkyl ammonium salt and thelike. These salts can be prepared by the conventional process, forexample from the corresponding acid and base or by salt interchange.

Examples of the esters are aliphatic esters, for example, lower alkylester e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester,butyl ester, isobutyl ester, t-butyl ester, pentyl ester,1-cyclopropylethyl ester, etc., lower alkenyl ester e.g. vinyl ester,allyl ester, etc., lower alkynyl ester e.g. ethynyl ester, propynylester, etc., hydroxy(lower) alkyl ester e.g. hydroxyethyl ester, loweralkoxy(lower)-alkyl ester e.g. methoxymethyl ester, 1-methoxyetyl ester,etc., and aromatic esters, for example, optionally substituted arylester e.g. phenyl ester, tosyl ester, t-butylphenyl ester, salicylester, 3,4-di-methoxyphenyl ester, benzamidophenyl ester etc.,aryl(lower)alkyl ester e.g. benzyl ester, trityl ester, benzhydrylester, etc. Examples of the amides are mono- or di- lower alkyl amidese.g. methylamide, ethylamide, dimethylamide, etc., arylamide e.g.anilide, toluidide, and lower alkyl- or aryl-sulfonylamide e.g.methylsulfonylamide, ethylsulfonylamide, tolylsulfonylamide etc.

Preferred examples of A include --COOH, --COOCH₃, --COOCH₂ CH₃,--COOCH(CH₃)₂ and --CONHSO₂ CH₃.

The configuration of the ring and the α- and/or omega chain in the aboveformula (I) may be the same as or different from that in the primaryPGs. However, the present invention also includes a mixture of acompound having a primary configuration and that of an unprimaryconfiguration.

Examples of the typical compounds of the present invention are15-keto-PGs, 13,14-dihydro-15-keto-PGs and their e.g.6-keto-derivatives, Δ² -derivatives, 3R,S-methyl-derivatives,5R,S-fluoro-derivatives, 5,5-difluoro-derivatives,16R,S-methyl-derivatives, 16,16-dimethyl-derivatives,16R,S-fluoro-derivatives, 16,16-difluoro-derivatives,17S-methyl-derivatives, 17R,S-fluoro-derivatives,17,17-difluoro-derivatives, 19-methyl-derivatives,20-methyl-derivatives, 20-ethyl-derivatives, 19-desmethyl-derivativesand 16-desbutyl-16-phenoxy derivatives.

When 15-keto-PG compounds of the present invention have a saturated bondbetween positions 13 and 14, these compounds may be in theketo-hemiacetal equilibrium by forming a hemiacetal between hydroxygroup at position 11 and ketone at position 15.

The proportion of both tautomeric isomers, when present, variesdepending on the structure of the rest of the molecule or kind of anysubstituent present and, sometimes, one isomer may predominantly bepresent in comparison with the other. However, in this invention, it isto be appreciated that the compounds used in the invention include bothisomers. Further, while the compounds used in the invention may berepresented by a structure or name based on keto-form regardless of thepresence or absence of the isomers, it is to be noted that suchstructure or name does not intend elimination of the hemiacetal type ofcompounds.

In the present invention, any of the individual tautomeric isomers, amixture thereof, or optical isomers, a mixture thereof, a racemicmixture, and other isomers such as steric isomers can be used in thesame purpose.

Some of the compounds used in the present invention may be prepared bythe method disclosed in Japanese Patent Publications (unexamined) No.A-52753/1989, A-104040/1989, A-151519/1989.

Alternatively, these compounds may be prepared by a process analogous tothat described herein or to known processes.

A practical preparation of the 15-keto compounds involves the followingsteps; referring to the Synthetic Charts I to III, reaction of thealdehyde (2) prepared by the Collins oxidation of commercially available(-)-Corey lactone (1) with dimethyl (2-oxoheptyl)phosphate anion to giveα,β-unsaturated ketone (3), reduction of the α,β-unsaturated ketone (3)to the corresponding saturated ketone (4), protection of the carbonylgroup of the ketone (4) with a diol to the corresponding ketal (5), anddeprotection of the p-phenylbenzoyl group to give the correspondingalcohol (6) followed by protection of the newly derived hydroxy groupwith dihydropyrane to give the corresponding tetrahydropyranyl ether(7). According to the above process, a precursor of PGEs wherein theω-chain is a 13,14-dihydro-15-keto-alkyl group is prepared.

Using the above tetrahydropyranyl ether (7),

6-keto- PGE₁ s (15) of which a group constituted with carbon atoms atpositions 5, 6 and 7 is --₅ CH₂ ₆ --C(O)₇ --CH₂ --, may be prepared inthe following steps; reduction of the tetrahydropyranyl ether (7) with,for example, diisobutyl aluminum hydride to give the correspondinglactol (8), reaction of the lactol (8), with the ylide generated from(4-carboxybutyl)triphenyl phosphonium bromide followed by esterification(10), cyclization between the 5,6-double bond and the hydroxyl group atposition 9 with NBS or iodine to give the halogenated compound (11),dehydrohalogenation of the compound (11) with, for example, DBU to givethe 6-keto compound (13) followed by Jones oxidation and removal of theprotecting groups.

Furthermore, PGE₂ s (19) of which a group constituted with carbon atomsat positions 5, 6 and 7 is --₇ CH₂ --₆ CH═₅ CH-- may be prepared in thefollowing steps; as shown in the Synthetic Chart II, reduction of theabove tetrahydropyranyl ether (7) to give the lactol (8), reaction ofthe resultant lactol (8) with the ylide derived from(4-carboxybutyl)triphenyl phosphonium bromide to give the carboxylicacid (16) followed by esterification to give ester (17), Jones oxidationof the esters (17) to give the compound (18), and removal of theprotecting groups.

Using the above tetrahydropyranyl ether (7) as the starting material,the compound having --₇ CH₂ --₆ CH₂ --₅ CH₂ -- may be prepared by usingthe same process as that for preparing PGE₂ having --CH₂ CH═CH-- andsubjecting the resultant compound (18) to catalytic reduction to reducethe double bond between the positions 5 and 6 followed by removal of theprotective groups.

Synthesis of 5,6-dehydro-PGE₂ s having --₇ CH₂ --₆ C.tbd.₅ C -- may becarried out by capturing a copper enolate formed by 1,4-addition of amonoalkylcopper complex or a dialkylcopper complex of the followingformulae: ##STR3## wherein G is alkyl, to4R-t-butyldimethylsilyloxy-2-cyclopenten-1-one with6-alkoxycarbonyl-1-iodo-2-hexyne or the derivatives.

The 11-β type PGEs can be prepared according to the Synthetic Chart III.

PGE derivatives having a methyl group at position 11 in place of hydroxycan be prepared by reacting a dimethyl copper complex with PGA-typecompound obtained by subjecting 9-hydroxy-11-tosylate to the Jonesoxidation. Alternatively, they can be prepared by protecting thecarbonyl of saturated ketone (4) produced by reducing unsaturated ketone(3), eliminating p-phenylbenzoyl and tosylating the produced alcohol,treating with DBU to form a lactol, introducing the alpha-chain byWittig reaction, oxidizing the alcohol at position 9 to give PGA-typecompound, and reacting the product with dimethyl copper complex in orderto introduce a methyl group into position 11 to give an11-methyl-PGE-type compound, which on reduction with e.g. sodiumborohydride gives an 11-methyl-PGF-type compound. An11-hydroxymethyl-PGE-type compound, is obtained by abenzophenone-sensitized photoaddition of methanol of PGA-type compound,which is reduced with, e.g. sodium borohydride, to give an11-hydroxymethyl-PGF-type compound. The 16-mono- or 16,16-di-halo typePGEs can be prepared according to the synthetic chart IV. The syntheticroute for the compounds used in the present invention is not limited tothe that described above one and may vary using different protecting,reducing and/or oxidizating methods.

Corresponding other PG compounds can be produced analogously. ##STR4##

Since the compounds used in the present invention have an activityuseful in prevention or therapy of insufficiency of gas exchangefunction in lungs and improving defensive ability of cells thereto orpreventing death of cells therefrom, these can be used for preparing amedicament for treating pulmonary dysfunction. Such activities can bemeasured by the standard methods such as potassium cyanide inducedcytotoxic hypoxia model or dyspnea model.

The compounds used in the present invention may be used as a medicinefor animals and human beings and usually applied systemically or locallyby such methods as oral administration, intravenous injection (includinginstillation), subcutaneous injection, suppository and the like. Whilethe dosage will vary depending on the particular animal or humanpatient, age, body weight, symptom to be treated, desired therapeuticeffect, administration route, term of treatment and the like,satisfactory effects will be obtained with the dosage of 0.001-500 mg/kgadministered in 2 to 4 divided doses a day or as a sustained form.

As a solid composition of this invention for oral administration,tablets, troches, buccals, capsules, pills, powders, granules and thelike are included. The solid composition containing one or more activesubstances is mixed with at least an inactive diluent, e.g. lactose,mannitol, glucose, hydrocypropyl cellulose, fine crystalline cellulose,starch, polyvinyl pyrolidone, magnesium aluminate metasilicate. Thecomposition may contain additives other than the inactive diluent, forexample, lubricants e.g., magnesium stearate, a disintegrator e.g.cellulose calcium gluconates, stabilizers e.g. α-, β- orγ-cyclodextrins, etherated cyclodextrins (e.g. dimethyl-α-, dimethyl-β-,trimethyl-β-, or hydroxypropyl-β-cyclodextrins), branched cyclodextrins(e.g. glucosyl- or maltosyl-cyclodextrins), formyl cyclodextrins,sulfur-containing cyclodextrins, misoprotols or phospholipids. Suchcyclodextrins may increase the stability of the compounds by forming aninclusion compounds. The stability may be often increased by forminglyposome with phospholipids. Tablets and pills may be coated with anenteric or gastroenteric film e.g. white sugar, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalates and thelike, if necessary, and furthermore they may be covered with two or morelayers. Additionally, the composition may be in the form of capsulesmade of substance easily absorbed e.g. gelatin. The composition may bein the form of buccals, when an immediate effect is desired. For thispurpose, base e.g. glycerine, lactose may be used.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs and thelike and contain a generally used inactive diluent e.g. purified wateror ethyl alcohol. The composition may contain additives e.g. wettingagents, suspending agents, sweeteners, flavors, perfumes andpreservatives.

The composition of the present invention may be in the form of sprayswhich may contain one or more active ingredients and which can beprepared according to a well known methods.

An injection of this invention for non-oral administration includessterile aqueous or nonaqueous solutions, suspensions, and emulsions.Diluents for the aqueous solution or suspension include, for example,distilled water for injection, physiological saline and Ringer'ssolution. Diluents for the nonaqueous solution and suspension include,for example, propylene glycol, polyethylene glycol, vegetable oils e.g.olive oil, alcohols, e.g. ethanol and polysorbates. The composition maycontain other additives, e.g. preservatives, wetting agents, emulsifyingagents, dispersing agents and the like. These are sterilized byfiltration through, e.g. a bacteria-retaining filter, compounding with asterilizer, gas sterilization or radiation sterilization. These can beprepared by producing a sterilized water or a sterilized solvent forinjection before use.

Another formulation according to the present invention is a rectal orvaginal suppository. This can be prepared by mixing at least one activecompound according to the invention with a suppository base e.g. cacaobutter and optionally containing nonionic surfactant for improvingabsorption.

The above pharmaceutical preparation can be used in the case of toxicheadache, increased irritability, confusion, vertigo, paropsia, nausea,syncope, coma, spasm, hypopnea, hyperidrosis, pyrexia, leucocytosis,bleeding tendency, albuminurea, tremor, drowsiness, hypertension etc.

The present invention also provides a method for treating disorder ofoxygen uptake into blood through lung.

A more complete understanding of the present invention can be obtainedby reference to the following Preparation Examples, Formulation Examplesand Test Examples which are provided herein for purpose of illustrationonly and are not intended to limit the scope of the invention.

Preparation Example 1

Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₁ methyl ester(39)

1-1) Preparation of(1S,5R,6R,7R)-6-hydroxymethyl-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one(29)

To a solution of commercial Corey lactone (THP-form, 37.9g) intetrahydrofuran was added a solution (1.0 M, 300 ml) oftetrabutylammonium fluoride in tetrahydrofuran and the resulting mixturewas stirred at room temperature for 3 hours.

Then the reaction mixture was concentrated under reduced pressure andthe residue was subjected to column chromatography to give the titlecompound (29). Yield: 21.70g (82.8%).

1-2) Preparation of(1S,5R,6R,7R)-6-{(E)-4,4-difluoro-5-oxo-2-octenyl}-7-tetrahydropyranyloxy-2-oxabicyclo-[3.3.0]octan-3-one(31)

A solution (2.0 M, 45.5 ml) of oxalyl chloride in methylene chloride wasdiluted with methylene chloride under an argon atmosphere at -78° C. Tothis solution was added dropwise dimethylsulfoxide (12.9 ml) and theresulting mixture was stirred for 10 minutes. A solution(1S,5R,6R,7R)-6-hydroxymethyl-7-tetrahyiropyranyloxy-2-oxabicylo[3.3.0]octan-3-one(29) (11.65 g) in methylene chloride was added dropwise and the mixturewas stirred for 30 minutes. Then triethylamine (56 ml) was addeddropwise and stirring was continued for further 1 hour. The reactionmixture was treated in the conventional manner to give the aldehyde (30)as a crude product.

To a solution of thallium ethoxide (3.26 ml) in methylene chloride wasadded under an argon atmosphere dimethyl3,3-difluoro-2-oxoheptylphosphonate (11.9 g) and the resulting mixturewas stirred for 1 hour. After cooling the solution to 0° C., a solutionof the aldehyde (30) obtained above in methylene chloride was addeddropwise to said solution and the mixture was stirred at roomtemperature for 14 hours. The reaction mixture was treated with aceticacid, celite and a saturated aqueous potassium iodide solution andfiltered. The filtrate was treated in the conventional manner and thecrude product was subjected to column chromatography to give the tilecompound (31). Yield: 7.787 g (44.3 %).

1-3) Preparation of(1S,5R,6R,7R)-6-(4,4-difluoro-5-oxoooctyl)-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one(32)

To a solution of(1S,5R,6R,7R)-6-{(E)-4,4-difluoro-5-oxo-2-octenyl}-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one(31) (5.57 g) in ethyl acetate was added 5% Pd/C (catalytic amount) andthe resulting mixture was shaken under a hydrogen atmosphere at roomtemperature for 7 hours. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure to give the tilecompound (32) as a crude product. Yield: 5.48 g (97.8%).

1-4) Preparation of (1S,5R,6R,7R)-6-(4,4-difluoro-5(RS)-hydroxyoctyl}-7-tetrahydropyranyloxy-2-oxabicyclo-[3.3.0]-octan-3-one (33)

To a solution of(1S,5R,6R,7R)-6-(4,4-difluoro-5-oxooctyl)-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one(32) (5.48 g) in methanol was added sodium borohydride (0.800 g) at 0°C. and the resulting mixture was stirred for 10 minutes. The reactionmixture was treated in the conventional manner and the obtained crudeproduct was subjected to column chromatography to give the titlecompound (33). Yield: 5.46 g (99.5%).

1-5) Preparation of16,16-difluoro-13,14-dihydro-11-O-tetrahydropyranyl-PGF₂α methyl ester(36)

A solution of(1S,5R,6R,7R)-6-{4,4-dihydro-5(RS)-hydroxyoctyl}-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]-octan-3-one(33) (2.579 g) in toluene was cooled to -78° C. under an argonatmosphere. To this solution was added dropwise a solution (1.5 M, 9.6ml) of diisobutylalmium hydride in toluene and stirred for 30 minutes.The reaction mixture was treated with methanol and a saturated aqueousRochelle salt solution. Then the solution was treated in theconventional manner to give the lactol (34) as a crude product.

To a suspension of 4-carboxybutyl triphenyl phosphine bromide (11.72 g)in tetrahydrofuran was added dropwise under an argon atmosphere asolution (1.0 M, 52.84 ml) of potassium tert-butoxide in tetrahydrofuranand the resulting mixture was stirred for 20 minutes. The solution wascooled to 0° C. and combined with a solution of lactol (34) intetrahydrofuran. The resulting mixture was stirred at room temperaturefor 15 hours and then treated in the conventional manner to give thecarboxylic acid (35) as a crude product.

To a solution of the carboxylic acid (35) in acetonitrile was addedunder an argon atmosphere 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.0ml) and methyl iodide (1.7 ml) and the resulting solution was stirred at60° C. for 30 hours. The solution was treated in the conventional mannerand the product was subjected to column chromatography to give the titlecompound (36). Yield: 2.737 g (84.5%).

1-6) Preparation of16,16-difluoro-13,14-dihydro-15-keto-11-O-tetrahydropyranyl-PGE₂ methylester (37)

To a solution of Collins reagent, prepared from cromic anhydride (16.18g) and pyridine (26.2 ml) in the conventional process, in methylenechloride was added a solution of16,16-difluoro-13,14-dihydro-11-O-tetrahydro-pyranyl-PGF₂α methyl ester(36) (2.646 g) in methylene chloride under an argon atmosphere at -20°C. The resulting mixture was stirred at the same temperature for 2 hoursand at -5° C. for 9 hours. The solution was treated with ether andsodium hydrogen sulfate and filtered. The filtrate was concentratedunder reduced pressure and the residue was subjected to columnchromatography to give the title compound (37). Yield: 1.890 g.(64.4%).

1-7) Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₂ methylester (38)

Into a mixed solvent of acetic acid : water : tetrahydrofuran (3:1:1)was dissolved16,16-difluoro-13,14-dihydro-15-keto-11-O-tetrahydroxypyranyl-PGE₂methyl ester (37) (2.809 g) and the resulting solution was stirred at60° C. for 5 hours. The reaction mixture was concentrated under reducedpressure and the residue was subjected to chromatography to give thetitle compound (38). Yield: 1.755 g (75.5%).

b 1-8) Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₁ methylester (39)

To a solution of 16,16-difluoro-13,14-dihydro-15-keto-PGE₂ methyl ester(38) (1.755 g) in ethyl acetate was added Pd/C (catalytic amount) andthe mixture was shaken under a hydrogen atmosphere at room temperaturefor 6 hours. The reaction mixture was filtered. The filtrate wasconcentrated and the residue was subjected to column chromatography togive the title compound (39). Yield: 1.655 g (93.8%).

¹ H NMR(CDCl₃) δ0.87(3H,t,J=7Hz), 1.15-2.05(23H,m), 2.11-2.30(3H,m),2.50(1H,dd,J=7.5 and 17 Hz), 3.10-3.20 (1H,br), 3.71(3H,s),4.05-4.20(1H,m) MS(DI-EI) m/z 404(M⁺), 355 (M⁺ -H₂ O-CH₃ O), 297(M⁺ -C₅H₉ F₂)

Preparation Example 2

Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₁ (39')

2-1) Preparation of(15RS)-16,16-difluoro-13,14-dihydro-11-O-tetrahydropyranyl-PGF₂.alpha.benzyl ester (36)

To a solution of16,16-difluoro-13,14-dihydro-11-O-tetrahydropyranyl-PGF₂α (35) (2.33 g)in dichloromethane (300 ml) were added DBU (2.1 ml) and benzyl bromide(2.2 ml) and the resulting mixture was stirred at room temperature for1.5 hour. The reaction mixture was treated in the conventional mannerand the crude product was purified by silica-gel column chromatographyto give the title compound (36). Yield: 2.522 g (96.1%)

2-2) Preparation of16,16-difluoro-13,14-dihydro-15-keto-11-O-tetrahydropyranyl-PGE₂ benzylester (37)

Collins reagent was prepared by using chromic anhydride (13.5 g) andpyridine (21.8 ml) in dichloromethane (300 ml), and to this were addedCelite (40 g) and(15RS)-16,16-difluoro-13,14-dihydro-11-O-tetrahydropyranyl-PGF₂.alpha.benzyl ester (36) (2.550 g). The reaction mixture was treated in theconventional manner and the crude product was purified by silica-gelcolumn chromatography to give the title compound (37). Yield: 1.991 g(78.6%)

2-3) Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₂ benzylester (38)

Into a mixed solvent of acetic acid:THF:water (3:1:1, 50 ml) wasdissolved16,16-difluoro-13,14-dihydro-15-keto-11-O-tetrahydropyranyl-PGE₂ benzylester (37) (1.550 g) and the solution was kept at 50° C. for 4 hours.The reaction mixture was treated in the conventional manner and thecrude product was purified by silica-gel column chromatography to givethe title compound (38). Yield 1.225g (92.9%)

2-4) Preparation of 16,16-difluoro-13,14-dihydro-15-keto-PGE₁ (39')

To a solution of 16,16-difluoro-13,14-dihydro-15-keto-PGE₁ benzyl ester(38) (0.844 g) in ethyl acetate (30 ml) was added 5% Pd/C and themixture was shaken under a hydrogen atmosphere. The reaction mixture wastreated in the conventional manner and the crude product was purified bysilica-gel column chromatography to give the title compound (43). Yield:0.404 g

¹ H NMR(CDCl₃) δ0.94 (t,3H,J=7.5 Hz), 1.20-2.70 (m,26H), 4.19 (m,1H),4.80 (br,2H). MS(DI-EI) m/z 390(M⁺), 372(M⁺ -H₂ O), 354(M⁺ -2H₂ O)

Formulation Example 1

(Powders for injection)

    ______________________________________                                                            (Parts by weight)                                         ______________________________________                                        13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.2                                                      1                                                       mannitol              5                                                       distilled water       0.4                                                     ______________________________________                                    

The above ingredients were mixed, stirred, sterilized, filtered andlyophilized to give powders for injection.

Formulation Example 2

(Injectable solution)

    ______________________________________                                                            (Parts by weight)                                         ______________________________________                                        13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1                                                      0.2                                                     nonion surfactant     2                                                       distilled water       98                                                      ______________________________________                                    

The above ingredients were mixed and sterilized to give and injectablesolution.

Formulation Example 3

(Enteric capsules)

13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE₂ (50mg) dissolved inmethanol (10 ml) was mixed with mannitol (18.5g). The mixture wasscreened (with a sieve, the pore size of which being 30 mm in diameter),dried at 30° C. for 90 minutes and screened again. The powders thusobtained were mixed with fine-grain silica gel (Aerosil^(*), 200 g) andfilled in No. 3 hard gelatin capsules (100) to give enteric capsuleswhich contain 0.5 mg of13,14-dihydro-15-keto-16,16-difluoro-20-ethyl-PGE₂ per capsule.

Formulation Example 4

(Powders for oral administration)

    ______________________________________                                                            (Parts by weight)                                         ______________________________________                                        13,14-dihydro-15-keto-16,16-difluoro-                                                                5                                                      PGF.sub.2α  methyl ester                                                light anhydrous silicic acid                                                                         5                                                      Abicel*               20                                                      lactose               70                                                      ______________________________________                                         *Trade Mark                                                              

The above ingredients were mixed to give powders for oraladministration.

Formulation Example 5

(Soft gelatine capsules)

    ______________________________________                                                           (Parts by weight)                                          ______________________________________                                        13,14-dihydro-15-keto-20-methyl-PGE.sub.2                                                           1                                                       methyl ester                                                                  light anhydrous silicic acid                                                                       899                                                      Panasate*             20                                                      ______________________________________                                         *Trade Mark                                                              

The above ingredients were mixed and filled in soft gelatine capsules.

Formulation Example 6

(Enteric capsules)

16-desbutyl-13,14-dihydro-15-keto-16-m-trifluoromethylphenoxy-PGF₂.alpha.methyl ester (50mg) dissolved in methanol (10ml) was mixed with mannitol(18.5g). The mixture was screened (with a sieve, the pore size of whichbeing 30 mm in diameter), dried at 30° C. for 90 minutes and screenedagain. The powders thus obtained were mixed with fine-grain silica gel(Aerosil*, 200g) and filled in No.3 hard gelatin capsules (100) to giveenteric capsules which contain 0.5mg of13,14-dihydro-15-keto-16-desbutyl-16-m-trifluoromethylphenoxy-PGF₂.alpha.methyl ester per capsule.

Formulation Example 7

(Powders for injection)

    ______________________________________                                                            (Parts by weight)                                         ______________________________________                                        13,14-dihydro-15-keto-16,16-difluoro-PGE.sub.1                                                      1                                                       mannitol              5                                                       distilled water       0.4                                                     ______________________________________                                    

The above ingredients were mixed, stirred, sterilized, filtered andlyophilized to give powders for injection.

Formulation Example 8

(Injectable Solution)

    ______________________________________                                                              (Parts by weight)                                       ______________________________________                                        13,14-dihydro-6,15-diketo-5R,S-fluoro-PGE.sub.1                                                       0.2                                                   nonion surfactant       2                                                     distilled water         98                                                    ______________________________________                                    

The above ingredients were mixed and sterilized to give and injectablesolution.

Formulation Example 9

(Powders for oral administration)

    ______________________________________                                                            (Parts by weight)                                         ______________________________________                                        13,14-dihydro-15-keto-16,16-difluoro-                                                               5                                                       19-desmethyl-PGE.sub.2 methyl ester                                           light anhydrous silicic acid                                                                        5                                                       Abicel*               20                                                      lactose               70                                                      ______________________________________                                         *Trade Mark                                                              

The above ingredients were mixed to give powders for oraladministration.

Formulation Example 10

(Soft gelatine capsules)

    ______________________________________                                                              (Parts by weight)                                       ______________________________________                                        13,14-dihydro-15-keto-16-desbutyl-16-m-                                                                1                                                    trifluoromethylphenoxy-PGE.sub.2 methyl ester                                 light anhydrous silicic acid                                                                          899                                                   Panasate*                20                                                   ______________________________________                                         *Trade Mark                                                              

The above ingredients were mixed and filled in soft gelatine capsules.

In the above formulation examples, the active ingredient can be replacedby any other compound within the compounds used in the invention.

Test Example 1

As the test animals, 10-12/group male Slc-ddY mice (5 weeks old, 27-30g) were used.

For subcutaneous administration, test compound was dissolved in Ringersolution in such amount that the obtained solution can be administeredat 10 ml/kg body weight.

The mice were divided according to their weight into groups with evenmean weight, each group consisting of 12 animals.

The mice received test compound in solution and after 5 minutes, 4 mg/kgKCN intravenously and survival time was measured based on heartbeat asan index.

The results are shown in the following Table 1.

                  TABLE 1                                                         ______________________________________                                                                  Survival Time                                              Dose     Number of (min.-sec.)                                                (mg/kg, s.c.)                                                                          Animals   Mean ± S.D.                                      ______________________________________                                        Control  0          12        9-32 ± 1-48                                  Compound 1                                                                             0.3        10        ** 16-42 ± 3-36                                       0.1        10        ** 13-09 ± 2-10                                        0.03      10        8-45 ± 1-16                                  ______________________________________                                         t-test: ** p < 0.01                                                           v.s. Control                                                                  Test Compound: 13,14dihydro-15-keto-16,16-difluoro-PGE.sub.2             

Test Example 2

As the test animals, 5/group male Crj:Wistar rats (7 weeks old, 200-250g) were used.

For subcutaneous administration, test compound was dissolved in thephysiological saline in such amount that the obtained solution can beadministered at 5 ml/kg body weight.

The test compound was subcutaneously administered at the dorsal skin.

After 30 minutes, ammonium sulfate [(NH₄)₂ SO₄ ] was intraperitoneallyadministered at a dose of 600 mg/kg and survival rate after 30 minuteswas measured. The results are shown in the following Table 2.

The control animals received the physiological saline. In this case,tonic convulsion derived from syspnea was observed after about 10minutes and all animals deceased within 30 minutes after administration.

                  TABLE 2                                                         ______________________________________                                                     Dose   Survival Rate                                                          (μg/kg)                                                                           (%)                                                       ______________________________________                                        Control        0         0                                                    Compound 1     1        20                                                                   10       80                                                    ______________________________________                                         t-test: ** p < 0.01                                                           v.s. Control                                                                  Compound 1: The same as in Test Example 1                                

Test Example 3

The procedure of Test Example 2 was repeated using other Test Compounds.The results are shown in Tables 3 and 4.

                  TABLE 3                                                         ______________________________________                                                     Dose   Survival Rate                                                          (μg/kg)                                                                           (%)                                                       ______________________________________                                        Control         0        0                                                    Compound 2     100      40                                                    ______________________________________                                         Compound 2: 13,14dihydro-15-keto-16,16-difluoro-PGE.sub.2 methyl ester   

                  TABLE 4                                                         ______________________________________                                                     Dose   Survival Rate                                                          (μg/kg)                                                                           (%)                                                       ______________________________________                                        Control         0       30                                                    Compound 2     100      60                                                    ______________________________________                                         Compound 3: 13,14dihydro-15-keto-16,16-difluoro-PGE.sub.1                

Test Example 4

As the test animals, 5/group male Crj:Wistar rats (7 weeks old, 200-250g) were used.

For subcutaneous administration, test compounds were dissolved in thephysiological saline in such amount that the obtained solution can beadministered at 5 ml/kg body weight.

The test compound was subcutaneously administered at the dorsal skin.

After 30 minutes, ammonium sulfate [(NH₄)₂ SO₄ ] was intraperitoneallyadministered at a dose of 600 mg/kg. After 30 minutes, survived animalswere sacrificed with chloroform and immediately after the lungs of theanimal were removed and weighed. The control animals received thephysiological saline and the lungs were weighed similarly.

Rate of inhibiting increase in weight of lung was calculated comparingthe weights of lungs from the animals treated with test compounds withthose from the control animals. The results are shown in Tables 5-13.

                  TABLE 5                                                         ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 1   10      48.2                                                                 100      66.1                                                     ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 2  100      102.8                                                    ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 3  10       49.0                                                     ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 4  100      75.2                                                     ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 5  100      79.8                                                     ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 6  100      46.5                                                     ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 7  100      46.5                                                     ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                                         Rate of Inhibiting                                                     Dose   Increase in Weight of Lung                                             (μg/kg)                                                                           (%)                                                          ______________________________________                                        Compound 8  100      45.7                                                     ______________________________________                                    

                  TABLE 13                                                        ______________________________________                                                             Rate of Inhibiting                                                   Dose     Increase in Weight of Lung                                           (μg/kg)                                                                             (%)                                                      ______________________________________                                        Compound 9  100      47.3                                                     ______________________________________                                         Test Compound:                                                                1: The same as above.                                                         2: The same as above.                                                         3: The same as above.                                                         4: 13,14dihydro-15-keto-16,16-difluoro-PGE.sub.1 methyl ester                 5:                                                                            6:                                                                            7: 13,14dihydro-15-keto-16,16-difluoro-11-dehydroxy-11-methyl-PGE.sub.2       methyl ester                                                                  8: 13,14dihydro-6,15-diketo-5,5-difluoro-PGE.sub.1 methyl ester               9: 13,14dihydro-15-keto-16,16-difluoro-PGF.sub.2α  methyl ester    

In the following data, NMR spectra were measured in CDCl₃ using HITACHIR-90H and mass spectra were measured by EI method at an ionizationpotential of 70 eV using HITACHI M-80B.

*13,14-dihydro-15-keto-16,16-difluoro-PGE₂

¹ H NMR (CDCl₃) δ0.93(t,3H,J=7.5 Hz), 1.20-2.70(m,24H), 4.20 (m,1H),5.40(m,2H)

MS(DI-EI) m/z 388(M⁺), 370(M⁺ -H₂ O), 352(M⁺ -2H₂ O)

*13,14-dihydro-15-keto-16,16-difluoro-19-desmethyl-PGE₂

¹ H NMR (CDCl₃) δ0.98(t,3H,J=7.5 Hz), 1.40-2.70(m,22H), 4.20(m,1H)5.40(m,2H)

MS(DI-EI) m/z 374(M⁺), 356(M⁺ -H₂ O), 338(M⁺ -H₂ O),

*13,14-dihydro-15-keto-16,16-difluoro-20-methyl-PGE₂

¹ H NMR (CDCl₃) δ0.90(t,3H,J=7.5 Hz), 1.20-2.70(m,26H), 4.20(m,1H),5.41(m,2H)

MS(DI-EI) m/z 402(M⁺), 384(M⁺ -H₂ O), 368(M⁺ -2H₂ O)

*13,14-dihydro-15-keto-16,16-difluoro-11-dehydroxy-11-methyl-PGE₂ methylester

¹ H NMR (CDCl₃) δ0.93(t,3H,J=7.5 Hz), 1.14(d,3H,J=6 Hz),

1.25-2.80(m,22H), 3.68(s,3H), 5.38(m,2H)

MS(DI-EI) m/z 400(M⁺), 369(M⁺ -CH₃ O)

*13,14-dihydro-6,15-diketo-5,5-difluoro-PGE₁ methyl ester

¹ H NMR (CDCl₃) δ0.88(t,3H,J=6.6 Hz), 1.10-1.40(m,4H),

1.45-2.20(m,10H), 2.20-3.15(m,11H), 3.67(s,3H), 4.00-4.18 (m,1H)

MS(DI-EI) m/z 418(M⁺), 400(M⁺ -H₂ O), 360(M⁺ -HF-H₂ O), 99(C₆ H₁₁ CO⁺)

What we claim is:
 1. A method for treatment of a pulmonary dysfunctionwhich comprises administering, to a subject in need of such treatment, apulmonary dysfunction treatment effective amount of a15-ketoprostaglandin compound represented by formula (I): ##STR5##wherein X and Y are hydrogen, hydroxy, halo, lower alkyl,hydroxy(lower)alkyl, or oxo, with the proviso that at least one of X andY is a group other than hydrogen, and 5-membered ring may have at leastone double bond, Z is hydrogen or halo, Z is --CH₂ OH, --COCH₂ OH,--COOH or its functional derivative, B is --CH₂ --CH₂, --CH═CH-- or--C.tbd.C--, R₁ is bivalent saturated or unsaturated, lower or mediumaliphatic hydrocarbon residue which is unsubstituted or substituted withhalo, oxo or aryl, R₂ is saturated or unsaturated, lower or mediumaliphatic hydrocarbon residue which is unsubstituted or substituted withhalo, hydroxy, oxo, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,aryl or aryloxy, and said compound represented by formula (I) having ahalogen atom at least at one of positions 5 and
 16. 2. The methodaccording to claim 1, in which the pulmonary dysfunction is based oncytotoxic hypoxia or dyspnea.
 3. The method according to claim 1, inwhich said 15-ketoprostaglandin compound is a 16-mono- ordi-halo-15-ketoprostaglandin compound.
 4. The method according to claim1, in which said 15-ketoprostaglandin compound is a13,14-dihydro-16-mono- or di-halo-15-ketoprostaglandin compound.
 5. Themethod according to claim 1, in which said 15-ketoprostaglandin compoundis a 13,14-dihydro-16-mono- or di-fluoro-15-ketoprostaglandin compound.6. The method according to claim 1, in which said 15-ketoprostaglandincompound is a 6,15-diketo-prostaglandin compound.
 7. The methodaccording to claim 1 for treatment of insufficiency of gas exchangefunction.
 8. The method according to claim 1 for treatment of pulmonaryedema.
 9. The method according to claim 1, wherein said pulmonarydysfunction is a condition having etiology based on or accompanied byinsufficiency of gas exchange function in the lungs.
 10. The methodaccording to claim 1, wherein said pulmonary dysfunction is a symptom ordisease characterized by disorder of permeation of oxygen contained inexpired gas into resorptive epithelium, disorder or permeation fromresorptive epithelium into blood via pulmonary capillary cells, ordisorder of uptake of oxygen into red cells.
 11. The method according toclaim 1, wherein said treatment comprises control of a disease in amammal, including preventing the disease, curing the disease, relievingthe disease and arresting or relieving the development of the disease.12. The method according to claim 1, wherein said 15-ketoprostaglandincompound is administered in an amount of 0.001-500 mg/kg in 2 to 4divided doses a day or as a sustained form.
 13. The method according toclaim 1, wherein said pulmonary dysfunction is dyspnea or hypopnea.